Wound treatment device

ABSTRACT

A wound treatment device comprising a water-impermeable envelope having at least one aperture. The envelope contains a therapeutic substance. The at least one aperture in the envelope is blocked by a material that breaks down in the presence of one or more active components of wound fluid thereby permitting the therapeutic substance to contact the wound fluid. Preferably, the aperture is blocked by a material that is a substrate for an enzyme present in would fluid, such as a protease.

CROSS-REFRENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. 371 ofPCT/GB2003/004118, filed 25 Sep. 2003, which claims priority fromGB0222527.4 filed Sep. 27, 2002, and U.S. Provisional Application Ser.No. 60/486,445 filed Jul. 14, 2003.

The present invention relates to articles that can provide controlleddelivery of one or more therapeutic agents to a wound.

The amount and composition of wound fluid (exudate) produced by a wounddepends on the type of wound and the history of wound healing. Forexample, surgical wounds have an acute inflammatory phase of a few daysduring which discharge is significant, after which the rate of exudateproduction can be expected to fall sharply. Chronic wounds, such asulcers, produce wound fluid containing elevated levels of proteaseenzymes. Infected wounds generally produce substantially more exudatethan non-infected wounds, and the composition of the wound fluid isdifferent. Burns produce large amounts of wound exudate havingcharacteristic properties.

Infection of wounds by bacteria delays the healing process, sincebacteria compete for nutrients and oxygen with macrophages andfibroblasts, whose activities are essential for the healing of thewound. Infection results when bacteria achieve dominance over thesystemic and local factors of host resistance. Infection is therefore amanifestation of a disturbed host/bacteria equilibrium in favour of theinvading bacteria. This elicits a systemic septic response, and alsoinhibits the multiple processes involved in wound healing. Lastly,infection can result in a prolonged inflammatory phase and thus slowhealing, or may cause further necrosis of the wound. The granulationphase of the healing process will begin only after the infection hassubsided.

Chronically contaminated wounds all contain tissue bacterial flora.These bacteria may be indigenous to the patient or might be exogenous tothe wound. Closure, or eventual healing of the wound is often based on aphysician's ability to control the level of the bacterial flora.

If clinicians could respond to wound infection as early as possible theinfection could be treated topically as opposed to having to useantibiotics. This would also lead to less clinicalintervention/hospitalisation and would reduce the use of antibiotics andother complications of infection.

Current methods used to identify bacterial infection rely mainly onjudgement of the odour and appearance of a wound. With experience, it ispossible to identify an infection in a wound by certain chemical signssuch as redness or pain. Some clinicians take swabs that are thencultured in the laboratory to identify specific organisms, but thistechnique takes time.

Pain is also associated with infected and chronic wounds. Biochemically,pain is experienced when there is an increase of kinins (bradykinin) inthe area of the wound. Kinins are produced by the proteolytic breakdownof kininogen, and the protease responsible for this is kallikrein.Kallikrein also stimulates the production of tissue plasminogenactivator (t-PA)

It is known to provide antimicrobial wound dressings. For example, suchdressings are known having a liquid-permeable wound contacting layer, anintermediate absorbent layer and an outer, liquid-impervious backinglayer, in which one or more of the layers contains an antimicrobialagent. For example, EP-A-0599589 describes layered wound dressingshaving a wound contacting layer of a macromolecular hydrocolloid, anabsorbent layer, and a continuous, microporous sheet intermediate thewound contacting layer and the absorbent layer. The absorbent layercontains a low molecular weight antimicrobial agent that can diffuseinto the wound.

Previous therapeutic (e.g. antimicrobial) wound dressings suffer fromthe drawback that the release of the therapeutic agent is relativelyunresponsive to the condition of the wound being treated. This isundesirable because all unnecessary medication can interfere with theprocesses of wound healing. In the case of antimicrobial wounddressings, unnecessary medication can result in resistantmicroorganisms.

There is thus a need for a wound treatment device that will selectivelyrelease therapeutic agents such as antimicrobial agents and/or painrelieving agents into wounds only when there is a clinical need. Such adevice could provide early intervention with suitable treatment (e.g. atopical antimicrobial treatment) before severe clinical symptoms orwound chronicity sets in.

In a first aspect, the present invention provides a wound treatmentdevice comprising a water-impermeable envelope having at least oneaperture, wherein the envelope contains a therapeutic substance, andwherein the at least one aperture in the envelope is blocked by amaterial that breaks down in the presence of one or more components ofwound fluid thereby permitting the active substance to contact the woundfluid.

The term “envelope” refers to a small package or enclosure that can beinserted onto or into a wound. It is preferably covered by a secondarydressing to hold it in place and provide absorbency for wound fluid. Thepackage is substantially impermeable to liquid water until the apertureis opened by the action of one or more components present in woundfluid. The envelope outside the aperture is normally formed from amaterial that is substantially impermeable to wound fluid, and thatpreferably does not break down in the presence of wound fluid. The woundfluid and/or the wound is thus not exposed to the therapeutic agentinside the envelope until the aperture is opened, and this enables thetreatment to be tailored to predetermined wound conditions andunnecessary medication to be avoided. The device can be used inconjunction with a wide range of existing wound dressings, and issufficiently small that it will not interfere with the absorbency ofsuch dressings.

In certain embodiments the envelope is formed substantially fromflexible sheet material. The sheet material is usually substantiallywater-impermeable (it may be permeable to water vapor, but not to liquidwater), and suitably it is substantially non-degradable or erodible inwound fluid. In this way the walls of the envelope around the enclosureare substantially impermeable to, and unaffected by, the wound fluid.Preferably, the envelope consists essentially of such sheet material,such as thermoplastic film, for example in the form of a sachet. Typicalfilm thicknesses are from about 10 to about 100 micrometers. Suitablethermoplastics include polyolefins such as polyethylene, copolymers suchas ethylene methyl acrylate, or fluoropolymers such as polyvinylidenefluoride. Such envelopes are extremely low cost and can be made in abroad range of sizes and shapes enabling them to be applied to all typesof wounds, including cavity wounds. Suitable sizes include envelopeshaving a maximum dimension of from about 2 mm to about 200 mm, forexample from about 5 mm to about 100 mm, typically from about 10 mm toabout 50 mm. Typical envelope configuration is a sachet formed bybonding together two sheets of film material (or one sheet folded over)around a periphery. Other suitable envelopes can be made from a web ortube of sheet material on form-fill-seal equipment.

Preferably, the aperture or apertures take up only a small part of thearea of the envelope, since the barrier materials are generally moreexpensive than the sheet materials used to form the envelope. In certainembodiments, the total area of the apertures in the envelope is fromabout 0.01 to about 1 cm². Preferably, the envelope has fewer than 10such apertures, more preferably fewer than 5, and most preferably onlyone such aperture. Typically, the apertures make up from about 0.1% toabout 50% of the surface area of the envelope, more typically from about1% to about 30%, and preferably from about 1% to about 10% of thesurface area of the envelope.

The mean area of each aperture may for example be from about 1 to about400 mm², preferably from about 2 to about 200 mm², and more preferablyabout 10 to about 100 mm².

The apertures in the envelope are blocked by a material that breaks downin wound fluid to open the apertures. The breakdown of the barriermaterial may be by dissolution, or by enzymatic or other chemicaldegradation by the ingredients of wound fluid. In certain embodiments,the barrier material breaks down preferentially in heavily exudingwounds. In certain embodiments, the degradable material breaks downpreferentially in infected wounds.

For example, the barrier material may comprise a water soluble material,such as a water soluble macromolecule. At medium to high levels ofexudate the soluble material is dissolved by the exudate, thus openingthe apertures. At low levels of exudate or where there is a dry woundthe soluble material will stay in place so that the apertures in thedevice remain occluded.

Suitable soluble materials for partially or completely occluding theapertures include water soluble macromolecular materials (hydrogels)such as sodium alginate, sodium hyaluronate, alginate derivatives suchas the propylene glycol alginate described in EP-A-0613692, and solublehydropolymers formed from vinyl alcohols, vinyl esters, vinyl ethers andcarboxy vinyl monomers, meth(acrylic) acid, acrylamide, N-vinylpyrrolidone, acylamidopropane sulphonic acid, PLURONIC (Registered TradeMark) (block polyethylene glycol, block polypropylene glycol)polystyrene-, maleic acid, NN-dimethylacrylamide diacetone acrylamide,acryloyl morpholine, and mixtures thereof. Suitable hydrogels are alsodescribed in U.S. Pat. No. 5,352,508.

Other suitable materials for occluding the apertures of the device arepolymeric materials that are not soluble in water, but that arebioerodible in wound fluid. Examples include polylactide/polyglycolidecopolymers, oxidized regenerated cellulose, chitosan, chitin, andmixtures thereof.

Other suitable materials for partially or completely occluding theapertures of the envelope are pH-sensitive materials that aresubstantially insoluble in water at 25° C. under acidic conditions, butsubstantially soluble in water at 25° C. under neutral or alkalineconditions. Whilst it is no simple matter to determine the actual pH ata wound site, it appears that the pH of chronic or infected wounds isneutral or slightly alkaline, whereas the pH of intact skin is slightlyacidic (pH 4 or 5).

Preferably, the pH-sensitive material is substantially insoluble inwater at 25° C. and pH 4 and substantially soluble in water at 25° C.and pH 8. Preferably, the polymer becomes soluble with increasing pH ata pH in the range of 5 to 7, more preferably 5.5 to 6.5. In this contextthe term “soluble” preferably denotes an equilibrium solubility of thematerial greater than 1% w/w in water at 25° C. Particularly suitableare film-forming polymers and mixtures, such as those used to provideenteric coatings on orally administered medicaments.

Preferably, the pH-sensitive material comprises a polymer selected fromthe group consisting of cellulose derivatives, starch derivatives,pectins, polyacrylates, polyvinyl acetate phthalate, and mixturesthereof.

Preferred cellulose derivatives are selected from cellulose acetatephthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose acetate succinate,carboxymethyl ethyl cellulose, oxidised regenerated cellulose, andmixtures thereof.

Preferred polyacrylates are selected from the copolymers of methacrylicacid with methyl methacrylate. Particularly preferred are variouscopolymers of this type sold under the Registered Trade Mark EUDRAGIT.By varying the ratio of methacrylic acid to methyl methacrylate it ispossible to control the pH at which these copolymers dissolve in orderto optimise the properties of the material.

In yet other embodiments, the degradable material occluding the aperturecomprises a substrate for an enzyme present in wound fluid.

For example, it has been discovered that wound fluid from infectedwounds, and from wounds that are apparently not clinically infected butwhich go on to become infected within a few days, have high levels ofneutrophil elastase activity and may also have high levels of otherinflammatory enzymes, such as macrophage proteases, other neutrophilproteases, bacterial collagenase, plasmin, hyaluronidase, kallikrein ort-PA. It is also known that the wound fluid produced by chronic woundssuch as diabetic ulcers, decubitis ulcers or venous ulcers, haveelevated levels of protease enzymes. Hence, the use of enzyme substratesenables the properties of the devices according to the present inventionto be responsive selectively to wound infection and wound chronicity.

Preferred enzyme substrates for use in the degradable material comprisea substance selected from the group consisting of elastin, fibronectin,collagen, crosslinked gelatin, fibrinogen, casein, hyaluronic acid,plasminogen, fibrin, chitin, chitosan, oxidized cellulose,polylactide/polyglycolide copolymers, and mixtures thereof.

In preferred embodiments, the materials for partially or completelyoccluding the apertures of the envelope comprise substrate materials forone or more protease enzymes present in wound fluid, especially infectedwound fluid. Such proteases include elastase, collagenase, pectinase,matrix metalloproteinases, and mixtures thereof. Preferred substratematerials include substances selected from the group consisting ofelastin, fibronectin, collagen, crosslinked gelatin, fibrinogen, casein,hyaluronic acid, plasminogen, fibrin, and mixtures thereof.

The barrier composition may comprise at least 25%, more preferably atleast 50% w/w based on the weight of the composition of the solublemacromolecular materials, ph-sensitive materials, or substrate materialson a dry weight basis. The barrier composition may further comprise fromabout 5 to about 50% by weight, preferably from 15 to 40% by weight, onthe same basis of one or more humectants and/or plasticisers such asglycerol, sorbitol or polyethylene glycol.

The one or more therapeutic agents may be any substance suitable for thetreatment of wounds. In certain embodiments the therapeutic agents areselected from the group consisting of antiseptics, antibiotics,analgesics, steroids and growth factors. Preferred therapeutic agentsare antimicrobial agents including metallic silver, silver salts andcompounds such as silver sulfadiazine, povidone iodine, chlorhexidineand mixtures thereof, and analgesic agents including benzocaine,lidocaine and mixtures thereof.

The therapeutic agent may be present in the envelope in particulate orsoluble or otherwise dispersible form, so that it can pass out of theenvelope into the wound once the aperture is opened by the action ofwound fluid. In other embodiments, the therapeutic agent may be retainedinside the envelope even after the aperture has opened, for example bybeing dispersed in or on a substrate that is too large to fit throughthe aperture. An example would be a silver treated cloth.

In certain embodiments the therapeutic material inside the envelope isadapted to provide sustained release of the therapeutic agent in woundfluid. For example, the material may comprise a bioerodible substancehaving the therapeutic agents dispersed or encapsulated therein.Suitable bioerodible substances include proteins such as albumin,collagen, cross-linked gelatin or zein, polysaccharides such as oxidizedregenerated cellulose, biodegradable synthetic polymers such aspolylactate/polyglycolate copolymers, glycosaminoglycans such ashyaluronate, and mixtures thereof.

In certain embodiments, the therapeutic material may be dispersed in oron particles suitable for drug delivery. The particles may be made byany suitable technique, including comminution, coacervation, ortwo-phase systems for example as described in U.S. Pat. No. 3,886,084.Techniques for the preparation of medicated microspheres for drugdelivery are reviewed, for example, in Polymeric Nanoparticles andMicrospheres, Guiot and Couvreur eds., CRC Press (1986). Themicroparticles are preferably loaded with from 1 to 90 wt. %, morepreferably from 3 to 50 wt. % of the therapeutic agents.

Preferably, the wound treatment device according to the presentinvention is sterile and packaged in a microorganism-impermeablecontainer.

In a second aspect, the present invention provides a wound dressingcomprising a wound treatment device according to the present invention.

In a third aspect, the present invention provides a method of treatmentof a wound comprising applying thereto a device according to the presentinvention. Preferably, the method further comprises applying a wounddressing over the device.

An embodiment of the present invention will now be described further, byway of example, with reference to the accompanying drawings, in which:

FIG. 1 shows a perspective view partially cut away of a wound treatmentdevice according to the invention; and

FIG. 2 shows a longitudinal cross-sectional view of the dressing of FIG.1.

EXAMPLE 1

Referring to FIG. 1, the wound treatment article 1 comprises an envelope2 of substantially liquid-impermeable sheet material. The envelopeconsists of front and back faces 3,4 of a continuous polypropylene filmthat are heat bonded around their and edge margin 5 to form a waterproofsachet. Inside the envelope there is a rectangular sheet 6 ofsilver-impregnated antimicrobial cloth. The envelope comprises anaperture 7 occluded by a collagenase-degradable film composition 8

The device is prepared as follows. 1 g of collagen fibers formed byfreeze drying Type I collagen extracted from limed bovine hide weresuspended in 100 ml of 0.05M acetic acid. This suspension was pouredinto a plastic dish to a thickness of 4 mm. The dish was placed in adrying cabinet at room temperature until the weight of the suspensionhad reduced to 50% of the initial weight. At this stage the aperturedpolymer sheet that will form the apertured face 3 of the envelope wasplaced on the surface of the collagen suspension. The suspension wasthen fully dried and peeled from the square dish. The resulting materialhas the aperture of the sheet occluded by a thin film of Type Icollagen. The apertured sheet 3 with the layer of collagen 8 appliedthereto was then assembled into the device by heat bonding to the backsheet 4, with the antimicrobial cloth inserted between the sheets 3 and4.

The device is packaged in a microorganism-impermeable pouch (not shown),and sterilised using gamma radiation.

In use, the device 1 is removed from the package, and the article isapplied to the wound and held in place by a sterile and absorbentsecondary dressing. The dissolution of the collagen contained in thebarrier layer 8 in the presence of elevated levels of collagenaseexposes the wound fluid to the antimicrobial silver cloth inside theenvelope in response to increased collagenase production by infected orchronic wounds.

EXAMPLE 2

In another embodiment, the barrier layer 8 contained chitosan as thebiodegradable component. The chitosan containing film compositionprepared as follows.

100.0 grams of chitosan chloride was mixed in 1.5 liters of water untilblended. 200.0 grams of glycerol were blended into the mixture, afterwhich 200.0 grams of polyethylene glycol (“PEG”) were then added. Theresulting mixture was then filtered and coated over the aperture asdescribed in Example 1. The mixture was then frozen and freeze dried, orair dried in circulating air at room temperature.

The above embodiments have been described by way of example only. Manyother embodiments falling within the scope of the accompanying claimswill be apparent to the skilled reader.

1. A wound treatment device comprising a water-impermeable envelopehaving one aperture, wherein the envelope contains a therapeutic agent,wherein the one aperture in the envelope is blocked by a degradablematerial that breaks down in the presence of one or more components ofwound fluid thereby permitting the therapeutic agent to contact thewound fluid, wherein the total area of the aperture in the envelope isfrom about 0.01 to about 1 cm², wherein the therapeutic agent isdispersed in or on a substrate larger than the total area of theaperture, wherein the therapeutic agent is retained inside the envelopeafter the aperture is opened, and wherein no part of the therapeuticagent contacts the wound surface.
 2. A wound treatment device accordingto claim 1, wherein the therapeutic agent is selected from the groupconsisting of antiseptics, antibiotics, analgesics, steroids and growthfactors, and mixtures thereof.
 3. A wound treatment device according toclaim 2, wherein the therapeutic agent is dispersed or encapsulated in abioerodible substance.
 4. A wound treatment device according to claim 3,wherein the bioerodible substance is selected from the group consistingof proteins, polysaccharides, biodegradable synthetic polymers,glycosaminoglycans, and mixtures thereof.
 5. A wound treatment deviceaccording to claim 2, wherein the therapeutic agent comprises anantimicrobial agent selected from colloidal silver, silver sulfadiazine,povidone iodine, chlorhexidine, and mixtures thereof.
 6. A woundtreatment device according to claim 2, wherein the therapeutic substanceis dispersed in or on a solid substrate.
 7. A wound treatment deviceaccording to claim 2, which is sterile and packaged in amicroorganism-impermeable container.
 8. A wound treatment deviceaccording to claim 1, wherein the degradable material comprises asubstrate for an enzyme present in wound fluid.
 9. A wound treatmentdevice according to claim 8, wherein the degradable material comprises asubstance selected from the group consisting of elastin, fibronectin,collagen, crosslinked gelatin, fibrinogen, casein, hyaluronates,plasminogen, fibrin, chitin, chitosan, oxidized cellulose,polylactide/polyglycolide copolymers, and mixtures thereof.
 10. A woundtreatment device according to claim 1, wherein the envelope is formedsubstantially from flexible sheet material.
 11. A wound treatment deviceaccording to claim 1, wherein the degradable material breaks downpreferentially in infected wounds.
 12. A wound dressing comprising awound treatment device according to claim 1.